The brain’s cleaning system can be boosted to reduce Alzheimer’s proteins

For the first time, drugs have been identified that boost our brain’s waste disposal system so it can better remove proteins linked to Alzheimer’s disease. Combining the therapy, which is commonly used as a sedative, with a drug that prevents dangerously low blood pressure appears to safely and effectively remove proteins associated with the disease, which could delay its onset by seven years.

“It’s a significant step forward,” he says Shiju Gu at Harvard University, who was not involved in the research. “It could benefit people with neurodegenerative disease, but even for healthy people, you could potentially use it to maximize brain function.”

Our brain removes metabolic waste through the glymphatic system, a network of channels surrounding blood vessels that pump waste fluid into the lymphatic system, where it is carried into the blood for disposal.

The glymphatic system is most active during the deeper stages of sleep, when slow brain waves help push waste fluid after it has been released from brain cells. But it gets worse with age, especially during Alzheimer’s disease.

Researchers have previously found that dexmedetomidine, a drug commonly used as a sedative during medical procedures, amplifies these brain waves in mice. That too improved the brain’s ability to clear waste fluids and slowed cognitive decline in mouse models of Alzheimer’s disease.

To investigate the effects of dexmedetomidine in humans, Paul Dagum at the pharmaceutical company Applied Cognition in Redwood City, Calif., and his colleagues recruited 19 adults—average age 60—who were sleep-deprived for one night in the lab. The morning after, the participants – who had no chronic medical conditions or brain problems – provided blood samples to act as a baseline measurement.

They were then given a 4-hour infusion of dexmedetomidine. They were also taking a drug called midodrine, which treats low blood pressure, a common side effect of dexmedetomidine. When they woke up, participants provided another blood sample.

A few weeks later, the researchers repeated the experiment, but this time the participants had a placebo pill and an infusion of saline. The researchers then compared the two post-nap blood samples, taking into account the differences in the two baseline samples.

It revealed that taking dexmedetomidine and midodrine, which the company collectively calls ACX-02, cleared two proteins, amyloid and tau, which are particularly prone to misfolding and clumping, more effectively than a placebo/saline intervention.

The team estimates that if ACX-02’s effect lasted for several years, it could delay the onset or worsening of Alzheimer’s by about seven years, based on the levels of misfolded amyloid typically seen in people who develop the condition, Dagum says. “This would be a significant and meaningful effect for those at risk,” adds the team member Jeff Iliff at the University of Washington in Seattle.

Further analysis revealed that ACX-02 appears to work by increasing the number of slow brain waves during the stage of sleep in which the brain transitions from a light to a deeper stage. It also appears to increase fluid flow through the brain so waste can be cleared more quickly. Finally, it appears to cause blood vessels to dilate and constrict more forcefully, which pushes fluid much harder along the glymphatic ducts, Iliff says.

Antibody therapies that remove amyloid plaques, such as lecanemab and donanemab, are approved in the US and UK, but do not have much effect on symptoms and can cause bleeding in the brain and swelling. “There is a huge need for new treatments – we know that the antibodies currently used for Alzheimer’s disease don’t really work and can cause serious side effects,” he says. Natalie Beschorner at the German Center for Neurodegenerative Diseases in Bonn.

No serious side effects were observed in Iliff’s study. Boosting the glymphatic system doesn’t activate the brain’s immune cells the way antibody therapies do, which quickly increases the risk of side effects, Dagum says. ACX-02 also removes amyloid beta and tau. This may mean its cognitive benefits are greater, Dagum says, adding that the team plans to test this in studies involving people with early-stage Alzheimer’s disease.

Gu admits that previous efforts to remove misfolded amyloid-beta and tau from the brains of people with Alzheimer’s have had limited benefit. However, he adds that if the new approach is safe and effective, it could be widely used. “It could benefit people with other brain conditions caused by the accumulation of misfolded proteins, such as Parkinson’s disease,” he says. It might even be possible to develop a pill form of dexmedetomidine to treat attention lapses after sleep deprivation, Iliff says.

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